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test the safety and efficacy of this new formulation in young children

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Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

The challenge

Lower respiratory tract infections are responsible for a huge burden of disease. Up to 17% of patients die during hospitalisation and a third of patients die within a month. Individuals with HIV infections are at particular risk of lower respiratory tract infections. A further challenge is the alarming growth in antibiotic resistance, leading to treatment failures.

There are multiple potential causes of lower respiratory tract infections, and treatment is typically empiric – based on knowledge of pathogens circulating locally and local patterns of antibiotic resistance rather than specific diagnostic tests. These methods lack sensitivity, and better approaches are needed to manage patients in low-resource settings, particularly those at high risk of poor outcomes.

In his Senior Fellowship, Dr William Worodria is aiming to generate a better understanding of the causes of pneumonia in a high-HIV setting in Uganda, the current state of antibiotic resistance, and key factors affecting clinical outcomes.

Focusing on emergency units at three public hospitals in Uganda, he is recruiting a cohort of pneumonia patients and collecting extensive data on the patients, their infections and their clinical progression. As well as using a range of conventional and molecular diagnostics to characterise infections, he is testing additional methods such as bronchoalveolar lavage as well as readily available point-of-care tests for blood markers associated with the severity of infection, such as C-reactive protein and procalcitonin. Monitoring of these markers could provide an early warning sign of treatment failure and the need for additional care or alternative treatments.

As well as shedding light on the local epidemiology of lower respiratory tract infections and drug resistance, this information will help to identify factors associated with treatment failures. Data will be used to develop simple-to-apply diagnostic algorithms for assessing the severity illness in low-resource settings and for triaging of patients, identifying those in need of most intensive care. Dr Worodria’s findings should also guide more appropriate use of antibiotics, reducing the risk of antibiotic resistance.

The Senior Fellowship will build Dr Worodria’s expertise, as well as clinical and laboratory capacity at participating centres. Dr Worodria will also be training one master’s and one PhD student through his project.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

Dr Worodria’s research will reveal key causes of community-acquired pneumonia in a high-HIV setting in sub-Saharan Africa, as well as the current state of antibiotic resistance. As well as generating new tools to improve clinical assessment and management of patients, the project will also create a foundation for future clinical trials on treatment of community-acquired pneumonia.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact